SK41297A3 - Method for preparing nitrobenzene derivatives - Google Patents

Abstract

PCT No. PCT/FR95/01241 Sec. 371 Date Mar. 28, 1997 Sec. 102(e) Date Mar. 28, 1997 PCT Filed Sep. 27, 1995 PCT Pub. No. WO96/10010 PCT Pub. Date Apr. 4, 1996A method for preparing a compound of formula (I), wherein R1 and R2, which are the same or different, are a hydrogen atom or an alkyl or alkoxy radical, or R1 and R2, taken together with the carbon atom to which they are attached, form a cycloalkyl radical containing 3-6 carbon atoms. The method comprises dehalogenating a derivative of formula (lI), wherein R1 and R2 have the same meanings as in formula (1) and Hal is a chlorine or bromine atom, using 1-2 mol of triethylammonium formate, in the presence of 0.002-0.1 mol of coal-borne palladium per mol of the compound of formula (II), in aceonitrile or tetrahydrofuran and at a temperature between 50 DEG C. and the boiling point of the reaction medium. <IMAGE> (I) <IMAGE> (II)

Description

Process for the preparation of nitrobenzene derivatives

Technical field

The invention relates to a process for the preparation of nitrobenzene derivatives of the general formula I

COOH (I) wherein R ¹ and R ² , which are the same or different, represent a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms or a straight or branched alkoxy group having 1 to 6 carbon atoms or R ¹ and R ² together with the carbon atom to which they are attached form a cycloalkyl group containing 3 to 6 carbon atoms, which are mainly useful as intermediates for the preparation of pharmaceutical products (WO 91/12264) or as antidotes for certain insecticides (US 4859232).

BACKGROUND OF THE INVENTION

These compounds are known to be prepared by acid hydrolysis of the corresponding nitriles, which in turn are obtained from the corresponding halogenated derivatives and an alkali metal cyanide (E. Felder, J. Med. Chem., 13,559 (1970) and US 4859232). However, the use of cyanide on an industrial scale can cause environmental pollution problems.

Alternatively, it is also known that the compounds can be prepared by dehalogenation of halogenonitrobenzenes using triethylammonium formate in the presence of palladium on carbon in a closed system without solvent and at 100 ° C (NACortese et al., J. Org. Chem., 42, 22, 3491-3494 (1977)). However, this process is difficult to carry out on an industrial scale due to the necessity of operating in a closed system at 100 ° C. In addition, when used in the preparation of compounds of formula I, it results in a mixture of three products (i.e. the desired product of formula I, the starting product and the dehalogenated product, but the nitro group is reduced to the amino group), which are difficult to separate, the yield of the desired product being low in this case.

An environmentally acceptable process has now been found which makes it possible to obtain pure compounds of the formula I in good yields.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of nitrobenzene derivatives of the general formula I, characterized in that

COOH (II)

Hal wherein R ¹ and R ² have the same meanings as in formula I, and Hal is a chlorine or bromine atom, dehalogenated at atmospheric pressure, using 1 to 2 mol of triethylammonium formate, in the presence of 0.002 and 0.1 mol Pd per mole of of a compound of formula II in acetonitrile or tetrahydrofuran and at a temperature between 50 ° C and the boiling point of the reaction mixture.

This reaction is preferably carried out under an inert atmosphere (e.g. nitrogen atmosphere).

It is particularly advantageous to use 1.5 moles of triethylammonium formate per mole of the derivative of the general formula II.

Triethylammonium formate can be formed in situ from 2 molar equivalents of triethylamine and 1.5 molar equivalents of formic acid.

Preferably, 5% palladium on carbon is used, in particular 0.01 mol of 5% palladium on carbon per mole of the compound of formula II.

The preferred amount of acetonitrile or tetrahydrofuran is between 5 and 15 equivalents by weight, based on the compound of formula II, and is in particular 10 equivalents.

A preferred reaction temperature is near 80 ° C.

The derivatives of formula (II) may be obtained by a modified form of the process described in DE 22100418 or by the destruction of the corresponding halogenated derivatives as described in the examples.

In the following, the method of the invention will be explained in more detail by means of specific examples thereof, these examples being illustrative only and not in any way limiting the scope of the invention, which is clearly defined by the definition of the claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

To a flask maintained under an inert atmosphere and containing

67.7 g of (RS) -2- (4-chloro-3-nitrophenyl) propionic acid, 87 ml of triethylamine and 6.1 g of 5% palladium on carbon in 680 ml of acetonitrile are added in 5 minutes 16.5 ml of acid formic acid. The reaction mixture thus obtained is heated to reflux for 18 hours, and after cooling to ambient temperature of 20 ° C, it is filtered through celite. The filtrate is evaporated to dryness under reduced pressure and the residue is taken up in 500 ml of water and 400 ml of ethyl acetate. The organic phase is decanted and the aqueous phase is extracted twice with 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate and concentrated to dryness under reduced pressure at 40 ° C. 53 g of acid are thus obtained

2- (3-nitrophenyl) propionic acid as a brown oil.

Infrared spectrum (CH ₂ Cl ₂ , cm ^-1 ):

γΟΗ acids: 3250 - 2450, yCH alifat .: 2985-2940, yC = O: 1715, y NO ₂ : 1535, ys NO ₂ : 1355, ym-subst-phenyl: 690,

Nuclear Magnetic Resonance Spectrum (DMSO-d6, 200 MHz):

1 45 (d, J = 7) Hz , 3H), 3 9 (q, J = Hz) , 1 H), 7 6 (t, J = 7) Hz, 1H), 7 8 (d, J = 7) Hz, 1H), 8 1 (d, J = 7) Hz, 1H), 8 15 (S, 1 H), 12 5 (Bs, OH acid).

2- (4-chloro-3-nitrophenyl) propionic acid can be prepared as described in DE 2210418.

Example 2

Using a method analogous to that described in Example 1, but starting from 6.3 g of 2- (4-chloro-3-nitrophenyl) -2-methylpropionic, 7.62 ml of triethylamine, 0.6 g of 5% palladium on charcoal and 1.46 ml formic acid in 100 ml acetonitrile. 5.0 g of 2- (3-nitrophenyl) -2-methylpropionic acid are thus obtained in the form of an orange oil.

Nuclear Magnetic Resonance Spectrum (DMSO-d6, 200 MHz):

1.57 (s, 6H);

7.75 (t, J = 7Hz, 1H);

7.9 (d, J = 7Hz, 1H).

8.13 (d, J = 7Hz, 1H);

8.15 (s, 1 H),

12.5 (broad s, OH of acid).

2- (4-Chloro-3-nitrophenyl) -2-methylpropionic acid can be prepared as follows. To a suspension of 5.35 g of 2- (4-chlorophenyl) -2-methylpropionic acid in a solution of 50 ml of concentrated sulfuric acid, cooled to a temperature close to 5 ° C, is added dropwise a solution containing 2.65 g of potassium nitrate in 10 ml of concentrated sulfuric acid, maintaining the reaction temperature at said temperature. Stirring was continued for one hour, and the reaction mixture was poured into 250 g of crushed ice with stirring. The white solid obtained is collected by filtration, washed twice with 100 ml of water and air-dried. There was thus obtained 2- (4-chloro-3-nitrophenyl) -2-methylpropionic acid (6.4 g) melting at 157 ° C.

Comparative example carried out using a method according to Cortensa

Keep the flask under an inert atmosphere containing 1 g of (RS) -2- (4-chloro-3-nitrophenyl) propionic acid, 0,9 ml triethylamine, 90 ml 5% palladium on carbon and 0,2 ml formic acid. 4 hours with stirring at a temperature near 100 ° C. After cooling to a temperature in the region of 20 DEG C., the compacted reaction mixture is taken up in 20 ml of methylene chloride and then filtered through celite. The filtrate is washed successively with 10 ml of a 1N aqueous hydrochloric acid solution and 10 ml of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure at 40 ° C. 0.97 g of a brown oil consisting of a mixture of (RS) -2- (4-chloro-3-nitrophenyl) propionic acid and (RS) -2- (3-aminophenyl) propionic acid in a molar ratio (expressed as a percentage) is obtained. 25: 70: 3.

Claims (10)

PATENT CLAIMS A process for the preparation of nitrobenzene derivatives of the general formula I R ¹ R 2 ° ^{2 N} T ^JfXx ir ^ ^{'C 00H} (I) wherein R ¹ and R ² are the same or different, are H or a linear or branched alkyl group having 1 to 6 carbon atoms or straight-chain or branched alkoxy containing 1 to 6 carbon atoms or R ¹ and R ² together with the carbon atom to which they are attached form a cycloalkyl group having 3 to 6 carbon atoms, characterized in that the derivative of the general formula II in which R ¹ and R ² have the same as in formula I and Hal is chlorine or bromine, dehalogenates at atmospheric pressure, using 1 to 2 moles of triethylammonium formate in the presence of 0.002 to 0.1 moles of palladium on carbon per mole of compound of formula II, in acetonitrile or tetrahydrofuran and at a temperature of from 50 ° C to the boiling point of the reaction mixture. Process according to Claim 1, characterized in that the reaction is carried out in an inert atmosphere. Process according to either of Claims 1 and 2, characterized in that 1.5 mol of triethylammonium formate is used per mole of the derivative of the general formula II. Method according to any one of claims 1 to 3, characterized in that the triethylammonium formate is formed in situ. Process according to any one of claims 1 to 4, characterized in that triethylammonium formate is formed from 2 molar equivalents of triethylamine and 1.5 molar equivalents of formic acid. Method according to one of claims 1 to 5, characterized in that 5% palladium on carbon is used. Process according to one of Claims 1 to 6, characterized in that 0.01 mol of 5% palladium on carbon is used per mole of the compound of the formula II. Process according to any one of claims 1 to 7, characterized in that 5 to 15 weight equivalents of acetonitrile or tetrahydrofuran, based on the compound of the formula II, are used. The process according to claim 8, wherein 10 equivalents of acetonitrile or tetrahydrofuran are used. Process according to any one of claims 1 to 9, characterized in that the reaction is carried out at a temperature of 80 ° C.